Biomedical subjects

William W Au

Publications and source records attributed to William W Au.

At least 19 recordsLinked to original sources

PubMed2006

Usefulness of biomarkers in population studies: from exposure to susceptibility and to prediction of cancer.

From a review of decades of intensive biomarker research and prospective validation studies, it becomes clear that only a limited number of biomarkers can be used to provide reliable documentation of excessive exposure to environmental mutagenic agents, expression of detrimental biological effects from the exposure and increased risk for cancer. These studies also demonstrate that expression of each biomarker represents an integrated response to the exposure that is influenced by susceptibility factors, and an integral component of the complex carcinogenic pathway. A current interest is in the use of phenotypic functional assays to improve and complement the assessment of cancer risk. A recommended approach includes assays that indicate DNA repair deficiency, i.e. host-cell-mediated reporter gene and challenge (mutagen-sensitivity) assays. The usefulness and limitations in biomarker investigations will be discussed. The review emphasizes the need for carefully designed investigations that involve adequate sample sizes and a combination of appropriate biomarkers to generate reproducible results that can be translated into more reliable cancer risk assessment. The assessment can be used to drive the implementation of disease prevention and intervention activities. Such an approach is consistent with the current priority in translating basic science knowledge into health applications.

Biomarkers↗

PubMed2006

Environmental risk factors for prevention and molecular intervention of cervical cancer.

Cervical cancer (CC) is potentially the most preventable and treatable cancer in human but it is a leading cause for cancer morbidity and mortality in women around the world. Therefore, more innovative prevention and treatment protocols need to be developed and implemented. With better understanding of the etiology of the disease, specific prevention protocols that involve life-style modifications to minimize the impact of environmental risk factors can be developed. It may be necessary to implement unique modification protocols for different countries. In addition, antiviral vaccine is a highly promising prevention approach. With respect to therapy, the development of more specific protocols that have fewer side effects is needed. With the availability of sophisticated molecular techniques, a new generation of targeted approach that has the potential to generate outstanding efficacy is being tested. Using the siRNA technology against the expression of human papillomavirus oncogenes, specific biological pathways that are essential to the growth and survival of the CC cells can be interrupted. Another promising approach is the molecular intervention of the estrogen pathway by blocking the expression of estrogen receptors. These molecular techniques may work by reactivating endogenous regulatory processes, e.g., the core apoptotic machinery, that can cause self-destruction of the CC cells, thus providing potentially effective molecular therapy. These topics are discussed in this review.

Environment↗

PubMed2006

Inhibition of growth of cervical cancer cells using a dominant negative estrogen receptor gene.

OBJECTIVE: Estrogen stimulates human papilloma virus oncogene expression, promotes cervical cancer (CC) cell proliferation and prevents apoptosis. Therefore, blockage of estrogen function may have therapeutic application to CC. METHODS: CasKi CC cells were transfected with an adenovirus expressing a dominant negative estrogen receptor gene (Ad-ER-DN) and their responses were investigated by RT-PCR, Flow Cytometry and Western blot assays. RESULT: Transfected cells showed disturbance of cell colony morphology, reduced HPV E6 and E7 mRNA, interruption of cell proliferation, reduced cyclin D1 protein and expression of apoptosis. CONCLUSION: We report, for the first time, the use of Ad-ER-DN to block estrogen receptors which led to dramatic changes in CC cells that are consistent with the possible reactivation of cellular p53 and Rb function. Their reactivation most likely allowed the recognition of existing chromosome abnormalities as a serious stress signal and the initiation of a cascade of cellular events in response to the stress, including the activation of the core apoptotic machinery which led to self-destruction of the CC cells.

Adenoviridae↗

PubMed2006

Heritable susceptibility factors for the development of cancer.

High frequencies of inherited DNA sequence variations (polymorphisms) are found in the human population. The involvement of polymorphic genes (especially for chemical metabolism and DNA repair) in the development of cancer is under intensive investigation. In our studies, we have irradiated blood lymphocytes from normal non-smokers with gamma-rays or UV-light to investigate genotypes and DNA repair functions. We found that XRCC1 399Gln and XRCC3 241Met were deficient in the repair of gamma-ray-but not UV-light-induced DNA damage that led to the expression of chromosome aberrations; therefore the variant genotypes are defective in base excision repair. The reverse was found with XPD 312Asn and XPD 751Gln; therefore they are defective in nucleotide excision repair. XRCC1 194Trp, OGG1 326Cys and APE1 148Glu had no DNA repair deficiency based on our experimental conditions. In another study, we investigated the role of some of these genes on the development of lung cancer. We found a significant increase of chromosome aberrations in patients and controls that had the XPD 751Gln and GSTM1 null genotypes, indicating a mechanistic causation of the disease. Therefore, inheritance of susceptibility genes can have significant impact on disease burden in the population. On the other hand, there are many questions that need to be addressed in order to evaluate the impact of susceptibility on cancer. These questions include the understanding of combinations of different polymorphic genes for susceptibility and of specific disease susceptibility for different ethnic populations.

Cocarcinogenesis↗

PubMed2006

Cytogenetic challenge assays for assessment of DNA repair capacities.

Different challenge assays have been used to investigate cellular responses following exposure to DNA damaging agents. Our protocol uses X- or gamma-rays or ultraviolet light to challenge cells to repair the induced damage, and chromosome aberrations as a biomarker to indicate DNA repair proficiency. The assay was used successfully to demonstrate base- and nucleotide-excision repair deficiency in certain polymorphic DNA repair genes, namely XRCC1 751Gln and XPD 312Asn, respectively. In addition, populations with elevated exposure to certain environmental mutagenic agents-cigarette smokers, pesticide sprayers, and residents who lived near uranium mining and milling sites-showed DNA repair deficiency. Because expression of chromosome aberrations is associated with a significantly increased incidence of both cancer morbidity and mortality, the challenge assay may be useful in predicting cancer risk. The protocol for the assay is straightforward and the data have practical applications.

Cells, Cultured↗

PubMed2005

Towards the world-wide ban of indoor cigarette smoking in public places.

In 1984, Dr. C. Everett Koop, then Surgeon General of the US, presented an important speech on the hazards of smoking. In his speech, he stated "The ultimate goal should be a smoke-free society by the year 2000." In addition, the World Health Organization (WHO) has initiated a process to ban smoking globally; on 21 May 2003, at the 56th World Health Assembly, WHO's 192 Member States unanimously adopted the world's first public health treaty, the WHO Framework Convention on Tobacco Control. Although good progress has been made, reaching the ultimate goal is far from certainty. Therefore, it is time to re-visit this crucial public health activity and re-energize the effort to reach this goal. Since numerous reports have been written on the ban of smoking based on benefits to the smokers, the emphasis of our report is on benefits to non-smokers from their exposure to environmental tobacco smoke (ETS). We provide a concise review of the impact of ETS on health and economy. In addition, we examined the different interest groups on supporting and opposing the ban, the role of the government, private citizens and medical professionals on this activity, and certain constraints on implementing the global ban. We also provide some recommendations on how to promote the ban globally. Since cigarette smoking is an unnecessary habit that has devastating consequences around the world, banning of cigarette smoking should be a global mission. A global ban on indoor smoking in public places is an important first step in an international effort to prevent morbidity and mortality caused by tobacco smoking and ETS.

Child↗

PubMed2005

Polymorphism in DNA repair genes and oral squamous cell carcinoma in Thailand.

DNA repair capacity is essential in maintaining cellular functions and homeostasis. However, the repair capacity can be altered based on DNA sequence variations in DNA repair genes and thus may cause cancer susceptibility. We investigated associations between polymorphisms in DNA repair genes and oral squamous cell carcinoma (OSCC) in a Thai population. Nine known single nucleotide polymorphisms (SNPs) in five common DNA repair genes were investigated: XRCC1 (Arg194Trp and Arg399Gln); XRCC3 (Thr241Met); XPC (PAT and Lys939Gln); XPD (exon 6, and Lys751Gln); and MGMT (Trp65Cys and Leu84Phe). We studied 106 cases and 164 healthy controls that were frequency-matched by age (+/-5 years), gender, and cigarette smoking and alcohol drinking habits. The genotype assays were performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The R version 2.0.1 statistical software was applied for statistical analysis of association. Based on multivariate analyses, we found that the variant genotypes with XRCC3 241Met exhibited a >3-fold elevated risk (OR = 3.3, 95% CI = 1.31-8.36, p = 0.01) for OSCC. There was a marginally significant risk observed in variants with XRCC1 194Trp (OR = 1.81, 95% CI = 0.91-3.63, p = 0.09) and XPD exon 6 (OR = 1.71, 95% CI = 0.93-3.16, p = 0.09). Combination of the variant genotypes of these three susceptibility genes was associated with a highly significant risk for OSCC (OR = 9.43, 95% CI = 1.98-44.9, p < 0.01). From further multivariate analyses, the variants with XRCC1 194Trp and possibly XRCC3 241Met interacted with tobacco and alcohol to further increase the risk (OR = 3.37 95% CI = 1.41-8.02, p < 0.01; OR = 2.92, 95% CI = 0.94-9.04, p = 0.06). On the other hand, increased risk was detected in non-betel chewers (OR = 2.88, 95% CI = 1.31-6.31, p < 0.01; OR = 2.61, 95% CI = 0.97-7.11, p = 0.06) who carry the two variant genotypes, respectively. Males with the variants XRCC1 194Trp or XRCC3 241Met had a higher risk of developing OSCC than males with the corresponding wild-type genotypes (OR = 2.72, 95% CI = 1.34-5.52, p < 0.01; OR = 2.95, 95% CI = 1.12-7.75, p < 0.05). Such association was not detected in females. Interestingly, the risk increased in female carriers of XPD exon 6 (OR = 3.93, 95% CI = 1.14-13.6, p < 0.05). We could not demonstrate a significant interaction of these SNPs with age in this study. Our data indicate that the variant genotypes with XRCC3 241Met and possibly XRCC1 194Trp and XPD exon 6 contribute to OSCC development in a Thai population. In addition, these SNPs influence the repair of DNA damage that is caused by environmental risk factors for oral cancer.

Aged↗

PubMed2005

Perspectives on the use of scientific knowledge for public health practice.

Achieving the goal of increasing quality and years of healthy life is fundamentally based on success in the practice of public health. As our life style changes with time and as public health issues become more global, the practice of public health is enhanced to meet new challenges. In addition to addressing infectious diseases, environmental concerns are gaining attention. New challenges require the modification of the methods of investigations, use of new technologies and application of real-time management of public health emergencies. In many situations, collaborations at the local, regional, national and global levels are needed. This manuscript provides a summary of the approaches to address certain crucial environmental health concerns towards the goal of increasing quality and years of healthy life.

Disaster Planning↗

PubMed2005

HLA-DQB1 and cervical cancer in Venezuelan women.

BACKGROUND: Cervical cancer represents a major health problem in Venezuela as well as in other Latin American countries. High-risk human papillomavirus (HR-HPV) infection is known as the major risk factor of cervical cancer. However, whether or not a HR-HPV-infected woman progresses to cervical cancer may depend on the immune system effectors induced by viral antigens presented by her specific human leukocyte antigens (HLA) alleles. The role of the HLA system in presenting peptides to antigen-specific T-cells may be critical for genetic susceptibility and genetic resistance to cervical carcinoma. OBJECTIVE: We aimed to investigate the relationship between HLA-DQB1, HPV infection, and cervical cancer in Venezuelan women. METHODS: Blood samples and cervical swabs were obtained from 36 patients and 79 healthy controls; additional cervical biopsies were obtained from all the patients. HPV DNA was detected by PCR and HLA-DQB1 genotyping was performed using a PCR-SSP protocol. RESULTS.: A positive association with cervical cancer was observed for HLA-DQB1*0201-0202 and *0402 alleles, however after Bonferroni correction only HLA-DQB1*0402 remained statistically significant (P value = 0.004, RR = 5.067). CONCLUSION: This is the first report of HLA-DQB1 alleles associated with cervical carcinoma in Venezuelan women. Larger studies are needed to assess whether these HLA-DQB1*0201-0202 and *0402 alleles have a direct effect on disease susceptibility.

Adult↗

PubMed2005

Biomarker research in occupational health.

OBJECTIVES: A variety of biomarkers have been used to study worker populations, and these studies have achieved different levels of success in the improvement of occupational health. METHODS: Successful application of biomarker research is dependent upon several important factors: ability to identify hazardous substances from the exposure to a variety of substances, relevance to the development of disease, and usefulness for health risk assessment. RESULTS: Besides the traditional biomarkers for exposure, biological effects, and health risk, new biomarkers for susceptibility and genome-wide responses are being used to improve our understanding of occupational health at a higher and, perhaps, more precise level. CONCLUSIONS: In addition, there is a continued need to develop and apply biomarkers that can be used to provide real-time detection of excessive exposure to hazardous substances in the workplace, especially from unexpected fugitive emissions. These topics are discussed in the review.

Benzene↗

PubMed2004

Life style, environmental and genetic susceptibility to cervical cancer.

We have studied cervical cancer (CC) patients from Venezuela and the US to elucidate the contribution of certain acquired and genetic susceptibility factors to the development of the disease. For acquired susceptibility factors, infection with high risk human papilloma virus (HPV), having multiple sex partners and having early sexual activities are significant risk factors for CC in Venezuela. The latter two are not significant risk factors for the US population. Infection with high risk HPV is a more significant risk factor for the US than the Venezuela populations. On the other hand, cigarette smoking is significantly associated with CC in the US but not the Venezuela populations. From genetic susceptibility factors, polymorphisms in the CYP2E1 and mEH genes are not associated with CC but the GSTM1 null genotype is for the US population. Our study indicates that the same susceptibility factors can have very different roles in the development of the same disease such as CC in different countries. The information is useful for the development of effective but different disease prevention programs for different countries in the control of CC.

Environment↗

PubMed2004

Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer.

We have previously investigated the role of polymorphic chemical metabolizing genes in the susceptibility to the development of lung cancer using 110 primary lung cancer patients and 119 matched smoker controls. Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer. In the present study, we have further evaluated a nested group of 79 patients and 69 matched controls, and observed that increased chromosome aberrations (CAs) were associated with variant DNA-repair genotypes among both the patient and the control groups, with a significant increase for individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients often had significantly increased CAs compared with controls with the same DNA-repair genotype and with similar cigarette smoking habits (< or =40 pack-years or >40 pack-years). Analyses of interactions between the DNA-repair and chemical-metabolizing genes indicated that the most significant interactions were between the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA from the interactions were often observed among patients with < or =40 pack-years, but not among those with >40 pack-years. Since some variant DNA-repair genotypes have functional deficits for DNA repair, the association between variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the development of lung cancer, with the DNA-repair genotypes interacting with variant chemical metabolizing genotypes to further increase the risk. The observation that patients had significantly increased CA frequencies compared with controls, irrespective of genotype, suggests that patients have additional factors that contribute to the development of lung cancer.

Aged↗

PubMed2004

Use of biomarkers to characterize functions of polymorphic DNA repair genotypes.

Inheritance of variant DNA repair genes is believed to influence individual susceptibility to the development of environmental cancer. However, the validity of the belief is dependent upon understanding the functions of the variant genes. Consequently, a variety of studies have been conducted to investigate the functions of variant DNA repair genes, e.g. using biomarkers. These studies on several representative polymorphic DNA repair genes are reviewed in this report. From a general overview, it appears that the biomarker investigations did not provide consistent observations. However, from a more careful evaluation, it is clear that the inconsistencies are probably caused by the use of populations and biomarkers that are not appropriate for investigating the repair activities of the genes. For example, the use of cigarette smokers and patients may not generate precise information for this type of investigations because these conditions can modify the functions of the investigated genes. Thus, the use of healthy non-smokers would be more appropriate. Other problems with these studies includes the small sample size used and the fact that some of the biomarkers used, such as sister chromatid exchanges, are not appropriate because the mechanisms for formation of the biomarkers and their biological significance are unknown. Nevertheless, the following conclusions can be derived from the review of the various biomarker studies that have been published. XRCC1 194Trp, OGG1 326Cys and APE1 148Glu probably have limited alterations in repair activities compared to the wild-type genotypes. XRCC1 399Gln and XRCC3 241Met are deficient in the repair of X-ray-, but not UV-light-induced chromosome aberrations, therefore the variant genes are defective in base excision repair. XPD 312Asn and XPD 751Gln are deficient in the repair of UV-light- but not X-ray-induced chromosome aberrations, therefore they are defective in nucleotide excision repair.

Biomarkers↗

PubMed2004

Health concerns regarding consumption of irradiated food.

Food irradiation is being promoted as a simple process that can be used to effectively and significantly reduce food-borne illnesses around the world. However, a thorough review of the literature reveals a paucity of adequate research conducted to specifically address health concerns that may directly result from the consumption of irradiated food. Consequently, there is considerable debate on the issue of health concerns from irradiated food among international agencies and between different nations. This report presents a critical review of scientific data and recommendations from different agencies and consumer groups. The objective of this review is to provide the scientific community and the general public with a balanced discussion on irradiated food from the viewpoint of an environmental or public health professional. As a result of this review, the authors conclude that current evidence does not exist to substantiate the support or unconditional endorsement of irradiation of food for consumption. In addition, consumers are entitled to their right of choice in the consumption of irradiated versus un-irradiated food. Different countries should further evaluate their local and global risks and benefits prior to developing and recommending national and international food irradiation policies.

Animals↗

PubMed2003

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia.

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.

Adolescent↗

PubMed2003

Acquired and genetic susceptibility to cervical cancer.

Infection with high-risk human papilloma virus (HPV) is a necessary risk factor for the development of cervical cancer (CC). However, there are many factors that contribute to the development of CC. We have been investigating the role of polymorphisms in chemical metabolizing genes and life-style factors in the development of CC between two countries with significantly different prevalence of CC. Our data confirm that infection with high-risk HPV is the most significant risk factor for CC in both Venezuela and US. In Venezuela, having multiple sex partners and early sexual activities are significant risk factors (OR=4.7, 95% CI=1.7-13.1; OR=6.7, 95% CI=2.3-20.1, respectively). On the other hand, cigarette smoking is the significant risk factor for women in the US (OR=6.4, 95% CI=1.8-23.2). Genotype analyses were conducted using specimens from the US population only. The GSTM1 null genotype was associated with a significant 3.4 fold increase in risk (95% CI=1.0-11.8) compared with those who were GSTM1 positive, after adjustment for smoking and HPV infection. Polymorphosis in CYP2E1 and mEH are associated with a non-significant increase in risk. Our study indicates that different acquired and genetic susceptibility factors can make significant contributions to the development of environmental disease such as cervical cancer.

Female↗

PubMed2003

International conferences on environmental mutagens in human populations-opportunities, accomplishments and challenges.

A major mission for organizing the series of International Conferences on Environmental Mutagens in Human Populations is to bring science and scientists to the sites where the field of environmental health is in developmental stages and environmental health is a serious concern. The mission has been fulfilled in each of the previous conferences that were held in Egypt, Czech Republic, Thailand and Brazil. These conferences have led to significant enhancement of regional scientific expertise from the acquisition of scientific knowledge and from the generation of sustainable collaborative programs.

Environment↗

PubMed2003

Mutagen sensitivity assays in population studies.

Human population monitoring studies are frequently conducted to determine if exposure to environmental mutagenic agents can cause health problems or not. In these studies, a variety of biomarkers are used to identify biological events that are predictive of health consequences. An emphasis in this report is on the use of mutagen sensitivity assays to understand health risk. The assay is based on the assumption that exposure to mutagenic chemicals or mixtures of chemicals for a long time can cause cellular changes that are expressed as mutagen sensitivity. From experience in using these assays in cancer patients and in mutagen-exposed populations, it is clear that the expression of mutagen sensitivity is based on the interactions between mutagen exposure and individual susceptibility. When studies are conducted under appropriate conditions, expression of mutagen sensitivity is suggestive of increased risk for environmental disease such as cancer.

Cell Cycle↗